Many neurotransmitters and hormones transduce their signal into a cell by activating G-protein-coupled receptors that modulate adenylyl cyclase; this changes intracellular cAMP levels which subsequently alters cAMP-dependent protein kinase (PKA) activity. A growing body of evidence from both the human and animal literature suggests that genetic variation of the cAMP/PKA system alters ethanol-seeking behavior and acute physiological responses to this drug. We have recently found that genetically altered mice completely lacking production of the RIIbeta subunit of PKA (RIIbeta -/-) showed increased consumption of 6%, 10%, and 20% (v/v) ethanol when compared to wild-type mice (RIIbeta +/+). Furthermore, the RIIbeta -/- mice are less sensitive to the sedative effects of ethanol as measured by duration of the loss of righting reflex. The main hypothesis to be tested is that PKA activity in specific brain regions modulates ethanol sensitivity and intake. As a strategy for delineating brain regions where RIIbeta subunit of PKA modulates ethanol sensitivity, Aim 1 will measure ethanol-induced c-Fos expression in RIIbeta -/- and RIIbeta +/+ mice. Aim 2 will determine if PKA signaling modulates voluntary ethanol consumption in brain regions where PKA signaling modulates sensitivity to the acute effects of ethanol. Parameters of ethanol ingestion and sensitivity will be determined in RIIbeta -/- and RIIbeta +/+ mice following infusion of cAMP/PKA stimulator (Sp-cAMPs) or inhibitor (Rp-cAMPs) into specific brain regions. Data collected during this project would provide a foundation for the future development of an R01 grant.